US8466202B2 - Anthracenedione compounds - Google Patents

Anthracenedione compounds Download PDF

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US8466202B2
US8466202B2 US12/816,223 US81622310A US8466202B2 US 8466202 B2 US8466202 B2 US 8466202B2 US 81622310 A US81622310 A US 81622310A US 8466202 B2 US8466202 B2 US 8466202B2
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Du-Shieng Chien
Yi-Wen Chu
Wu-Chang Chuang
Ming-Chung Lee
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Sun Ten Phytotech Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/105—Plant extracts, their artificial duplicates or their derivatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/12—Ketones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/10—Laxatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics

Definitions

  • Constipation a common and uncomfortable condition, affects about 20% of the population in the west. It is most often caused by a low-fiber diet, lack of physical activity, inadequate intake of water, or delay in going to the bathroom. Stress and travel also contribute to constipation. Other causes include bowel diseases (e.g., inflammatory bowel disease and irritable bowel syndrome), cystic fibrosis, pregnancy, mental health problems, or medication.
  • bowel diseases e.g., inflammatory bowel disease and irritable bowel syndrome
  • cystic fibrosis e.g., pregnancy, mental health problems, or medication.
  • This invention relates to compositions and methods for treating constipation.
  • this invention relates to a pharmaceutical composition, either in a dry form or a solublized from, containing a pharmaceutically acceptable enteric carrier and an anthracenedione compound of formula (I):
  • each of R 1 and R 2 independently, is H, C 1 -C 6 alkyl, or C(O)R a ; each of R 3 , R 5 , R 6 , and R 8 , independently, is H, C 1 -C 6 alkyl, or OR b ; and each of R 4 and R 7 , independently, is H, OR c , COOR c , OC(O)OR d , SR d , NHR d , or C 1 -C 6 alkyl optionally substituted with C 3 -C 20 cycloalkyl, C 1 -C 20 heterocycloalkyl, aryl, heteroaryl, OR c7 COOR d , OC(O)OR d , SR d , or NHR d ; in which each of R a and R c is C 1 -C 10 alkyl; and each of R b and R d , independently, is H or C 1 -C 10 alkyl.
  • the compounds described above include their pharmaceutically acceptable salts and their metal complexes.
  • the salts can be formed, e.g., between a negatively charged oxygen in a compound and a positively charged inorganic or organic ion.
  • the metal complexes can be formed, e.g., the oxygen atoms on the compounds coordinate with one or more metallic ions.
  • each of R 4 and R 7 is H, C 1 -C 6 alkyl (e.g., CH 3 ), or OR c (e.g., OCH 3 ).
  • each of R 1 , R 2 , R 3 , R 5 , R 6 , and R 8 can be H.
  • Exemplary anthracenedione compounds include chrysophanol and physcion:
  • alkyl refers to a saturated or unsaturated, linear or branched hydrocarbon moiety, such as —CH 3 , —CH 2 —CH ⁇ CH 2 , or branched —C 3 H 7 .
  • cycloalkyl refers to a saturated or unsaturated, non-aromatic, cyclic hydrocarbon moiety, such as cyclohexyl or cyclohexen-3-yl.
  • heterocycloalkyl refers to a saturated or unsaturated, non-aromatic, cyclic moiety having at least one ring heteroatom (e.g., N, O, or S), such as 4-tetrahydropyranyl or 4-pyranyl.
  • aryl refers to a hydrocarbon moiety having one or more aromatic rings.
  • aryl moieties include phenyl, phenylene, naphthyl, naphthylene, pyrenyl, anthryl, and phenanthryl.
  • heteroaryl refers to a moiety having one or more aromatic rings that contain at least one heteroatom (e.g., N, O, or S).
  • heteroaryl moieties include furyl, furylene, fluorenyl, pyrrolyl, thienyl, oxazolyl, imidazolyl, thiazolyl, pyridyl, pyrimidinyl, quinazolinyl, quinolyl, isoquinolyl, and indolyl.
  • Alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl mentioned herein include both substituted and unsubstituted moieties, unless specified otherwise.
  • Possible substituents on cycloalkyl, heterocycloalkyl, aryl, and heteroaryl include, but are not limited to, C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, C 3 -C 8 cycloalkyl, C 5 -C 8 cycloalkenyl, C 3 -C 20 cycloalkyl, C 1 -C 20 heterocycloalkyl, C 1 -C 10 alkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, amino, C 1 -C 10 alkylamino, C 1 -C 20 dialkylamino, arylamino, diarylamino, hydroxyl, halogen, thio, C 1 -C
  • alkyl examples include all of the above-recited substituents except C 1 -C 10 alkyl, C 2 -C 10 alkenyl, and C 2 -C 10 alkynyl. Cycloalkyl, heterocycloalkyl, aryl, and heteroaryl can also be fused with each other.
  • the anthracenedione compounds described above can be used to treat constipation, i.e., improve intestinal motility while maintaining normal intestinal function. Increased intestinal motility shortens the duration for food to stay in the intestine. As a result, the intestine absorbs less food, which often includes carbohydrate, fat, cholesterol, low density lipoprotein, or triglyceride. Accordingly, the anthracenedione compounds allow a subject to decrease the body's intake of these nutrients and thereby (i) decrease cholesterol or triglycerides levels or (ii) reduce or maintain the body weight. Thus, this invention also relates to a method of using these compositions to improve intestinal motility and maintain normal intestinal function, to decrease cholesterol, low density lipoprotein, or triglycerides levels, and to reduce or maintain the body weight.
  • this invention relates to a method of treating inflammatory bowel disease or irritable bowel syndrome using the above-mentioned anthracenedione compounds.
  • anthracenedione compounds described above in treating constipation, inflammatory bowel disease, or irritable bowel syndrome, improving intestinal motility and maintaining normal intestinal function, decreasing cholesterol, low density lipoprotein, or triglycerides levels, or reducing or maintaining the body weight; and (2) use of the anthracenedione compounds for the manufacture of a medicament or dietary supplement for the just-mentioned applications.
  • This invention is based, at least in part, on the unexpected discovery that two anthracenedione compounds, chrysophanol and physcion, found in Chinese herb Rheum palmatum Linne, are each effective in treating constipation. They do not have the side effects often seen in herb extracts prepared from the Rheum palmatum Linne, e.g., cramping, bloating, gas, and diarrhea. Further, each compound has a very low enteric absorption rate and therefore has minimal overall side effects to the body.
  • composition that contains an enteric carrier and one or more of the anthracenedione compounds described in the Summary section above.
  • An enteric carrier is designed to minimize any fast release of a drug upon oral administration until the drug reaches the intestine. See, e.g., U.S. Pat. Nos. 5,188,836 and 6,306,434.
  • the composition can be a pharmaceutical composition that contains a pharmaceutically acceptable carrier or a dietary composition that contains a dietary suitable carrier.
  • an anthracenedione compound is added to the composition in pure form or substantially pure form.
  • Anthracenedione compounds for use in this invention can be chemically synthesized or purified from herbs. For example, physcion and chrysophanol can be isolated from plants listed below in Tables A and B, respectively.
  • compositions of the present invention include, but are not limited to, foods, food additives, nutritional supplements, and pharmaceutical preparations. It may be in the form of tablets, suspensions, implants, solutions, emulsions, capsules, powders, syrups, liquid compositions, ointments, lotions, creams, pastes, gels, or the like.
  • a dietary composition of this invention contains one or more of the anthrecenedione compounds and an edible carrier. Additional nutrients, such as minerals or amino acids, may be included.
  • a dietary composition can also be a drink or food product. Examples of a drink product include, but are not limited to, tea-based beverages, juice, coffee, and milk. Examples of a food product include jelly, cookies, cereals, chocolates, snack bars, herbal extracts, dairy products (e.g., ice cream, and yoghurt), soy bean product (e.g., tofu), and rice products.
  • a pharmaceutical composition for oral administration can be any orally acceptable dosage form including capsules, tablets, emulsions and aqueous suspensions, dispersions, and solutions.
  • commonly used carriers include lactose and corn starch.
  • Lubricating agents such as magnesium stearate, are also typically added.
  • useful diluents include lactose and dried corn starch.
  • a composition of the present invention includes a carrier.
  • a carrier may be a suitable dietary carrier or a pharmaceutically acceptable carrier.
  • a pharmaceutically acceptable carrier include, but are not limited to, biocompatible vehicles, adjuvants, additives, and diluents to achieve a composition usable as a dosage form.
  • a “pharmaceutically acceptable carrier” refers to a carrier that, after administration to or upon a subject, does not cause undesirable physiological effects.
  • the carrier in a pharmaceutical composition must be “acceptable” also in the sense that it is compatible with the active ingredient and, preferably, capable of stabilizing it.
  • solubilizing agents can be utilized as pharmaceutical carriers for delivery of an active anthracenedione compound. Examples of other carriers include colloidal silicon oxide, magnesium stearate, cellulose, sodium lauryl sulfate, and D&C Yellow #10.
  • composition in any of the forms described above, can be used for treating constipation.
  • the composition increased the production of feces and feces water content in a subject without causing side effects such as diarrhea. Also, it was effective in reducing or maintaining the body weight of the subject.
  • treating refers to administering an effective amount an anthrecenedione compound to a subject that has a disorder, e.g., constipation, inflammatory bowel disease, or irritable bowel syndrome, or has a symptom of such a disorder, or has a predisposition toward such a disorder, with the purpose to cure, heal, alleviate, relieve, alter, remedy, ameliorate, improve, or affect the disorder, the symptoms of the disorder, or the predisposition toward the disorder.
  • administration covers oral delivery to a subject a composition of the invention in any suitable form, e.g., food product, beverage, tablet, capsule, suspension, and solution.
  • an “effective amount” refers to a dose of the composition that is sufficient to provide a physical benefit (e.g., increasing feces production and reducing the body weight) or a therapeutic benefit (e.g., lowering cholesterol levels). Both in vivo and in vitro studies can be conducted to determine optimal administration routes and doses.
  • Increasing feces production refers to an increase in the wet weight of feces produced by a subject by 15% or more one day after the subject receives an active composition as determined by the method described in Example 3 below or any analogous method.
  • a composition of the present invention may be used alone or in combination with other biologically active ingredients. It may be administered to a subject in a single dose or multiple doses over a period of time, generally by oral administration. Various administration patterns will be apparent to those skilled in the art.
  • the dosage ranges for the administration of the composition are those large enough to produce the desired effect.
  • the dosage should not be so large as to cause any adverse side effects, such as unwanted cross-reactions and the like.
  • the dosage will vary with the age, weight, sex, condition, and extent of a condition in a subject, and the intended purpose.
  • the dosage can be determined by one of skill in the art without undue experimentation.
  • the dosage can be adjusted in the event of any counter indications, tolerance, or similar conditions. Those of skill in the art can readily evaluate such factors and, based on this information, determine the particular effective concentration of a composition of the present invention to be used for an intended purpose.
  • the supernatant was fractionated in a Diaion HP-20 column and eluted with 30% ethanol, followed by 95% ethanol and ethyl acetate. Elutes fractionated from 95% ethanol (Fr-D) and from ethyl acetate (Fr-E) were combined with Fr-I as STD05. Twenty grams of STD05 was dissolved in ethyl acetate and mixed with a small amount of silica gel. Ethyl acetate was then removed under vacuum to give a mixture. The mixture was purified on a silica gel column eluting with 0% to 5% ethyl acetate in hexanes. Fractions thus obtained were analyzed by HPLC.
  • Rheum palmatum Linne extracts were studied.
  • a crude Rheum palmatum Linne extract and STD05 were obtained from SunTen Phytotech Co., Ltd. (Jhonghe City, Taiwan).
  • Commercial available laxatives, Through® Choung Mei Pharmaceutical Co., Ltd.; active ingredient: Sennosides 20 mg, as Sennosides A+B 12 mg, Lot. 009A 051) and Dulcolax® (Boehringer Ingelheim, Taiwan, Ltd.; active ingredient: Bisacodyl; Lot. 480-4942) were obtained from a pharmacy.
  • the experiments were carried out under conditions in which temperature, humidity, and lighting were all controlled. Each rat was fed standard rat food and water ad libitum in housing that provided a 12-hour light/dark cycle. The rats were divided into seven groups according to the body weights.
  • the first part of the experiment studied the effect of the above-mentioned extracts on feces production. During the three-week period, any rat that appeared dying was euthanized, dissected, and studied to check for any illness or injures. Any complications or illness were analyzed by H&E stains to determine the cause of death and to allow for dosage reconsiderations for future experiments.
  • Intestine motility data were expressed as mean ⁇ SD. Data were analyzed using the one-way ANOVA method. For comparison within the groups, a Post hoc Comparison was applied. In both feces production and intestine motility analyses, p ⁇ 0.05 indicates significant differences. For the feces production tests, the data for each group and each time point represent the total wet weight or pellet count of the six rats in the group.
  • Group I 6 rats, as negative control, were given no treatment; 6 rats, as positive control, were given 3.35 mg/kg/day Sennosides (Through®, Chung Mei Pharmaceutical Co., Ltd; Active ingredient: Sennosides 20 mg, as sennoside A+B 12 mg, Lot. 012F 006); 6 rats were treated STD05 (8 mg/kg/day); 6 rats were treated with an extract fraction containing aloe-emodin, rhein, and emodin (“ARE”, 8 mg/kg/day); 6 rats were treated with Aloe-emodin (4 mg/kg/day); and 6 rats were treated with Rhein (4 mg/kg/day).
  • mice were given no treatment; 6 rats, as positive control, were given 3.35 mg/kg/day Sennosides; 6 rats were treated STD05 (24 mg/kg/day); 6 rats were treated with an extract fraction containing ARE (24 mg/kg/day); 6 rats were treated with Chrysophanol (4 mg/kg/day); and 6 rats were treated with Emodin (4 mg/kg/day).
  • Group III 6 rats, as negative control, were given no treatment; 6 rats were treated with Physcoin (4 mg/kg/day); and 6 rats were treated with a mixture of chrysophanol and physcion (8 mg/kg/day, “CP”).
  • the first part of the experiment studied the effect of the test substances on feces production.
  • the rat's feces was also studied three times in the manner described above during the 10-day period for any unusual observations.
  • any rat that appeared dying was euthanized, dissected, and examined for any illness or injury. Any complications or illness were analyzed by H&E stains to determine the cause of death and to allow for dosage reconsiderations for future experiments.
  • Table 4 Summarized in Table 4 below are the effects of the compounds, mixtures, or extracts on the rat body weights.
  • physcion, CP, aloe-emodin, chrysophanol, rhein, and emodin increased the feces amount (wet weight) by 93%, 57%, 27%, 19%, 31%, and ⁇ 30%, respectively, at Day 1; by 57%, 39%, 9%, 16%, ⁇ 9%, and 12%, respectively, at Day 5; and by 32%, 18%, 20%, 14%, ⁇ 1%, and 4%, respectively, at Day 10.
  • the averages are 61%, 38%, 19%, 16%, 7%, and ⁇ 5%, respectively.
  • intestinal motility tests were conducted in the same manner described above. During dissection, any unusual observations were recorded and photographed. For comparison within the groups, a Post hoc Comparison was applied with p ⁇ 0.05 indicating significant differences. It was found that the rat received STD05 (containing Physcion and Chrysophanol) and Sennosides had greater intestinal motility (69.3% and 67.9%) than the control rats (61.1%).
  • STD05 was tested in Guinea pig ileum electrical stimulation increase tissue assay at test concentrations ranging from 10 nm to 10 ⁇ M by MDS Pharma Services.
  • the assay was conducted according to the method described in Moritoki, et al., “Effects of methylxanthines and imidazole on the contraction of guinea pig ileum induced by transmural simulation” Eur. J. Pharmacol. 35, 185-198.
  • STD05 was evaluated for possible hypocholesterolemic activity in hamsters fed with a high cholesterol diet. STD05 at 30 and 100 mg/kg was administered orally once a day for 14 consecutive days. Blood was drawn from overnight fasted hamsters on day 1 (pre-treatment), day 8 (7 days post dosing), and day 15 (14 days post dosing) to measure serum total cholesterol, high density lipoprotein, low density lipotprotein and triglyceride levels. Post-treatment values on day 8 and day 15 were expressed in percentage of respective pretreatment values (day) in order to assess lipid-lowering effect of the tested composition.

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Abstract

This invention relates compositions containing compounds of formula (I) below:
Figure US08466202-20130618-C00001
Each of R1, R2, R3, R4, R5, R6, R7, and R8 is defined in the specification.

Description

This application is a continuation of U.S. patent application Ser. No. 11/733,041, filed Apr. 9, 2007 now U.S. Pat. No. 7,767,719; which claims priority to U.S. Provisional Application No. 60/790,340, filed on Apr. 7, 2006. The contents of the above applications are incorporated herein by reference in their entirety.
BACKGROUND
Constipation, a common and uncomfortable condition, affects about 20% of the population in the west. It is most often caused by a low-fiber diet, lack of physical activity, inadequate intake of water, or delay in going to the bathroom. Stress and travel also contribute to constipation. Other causes include bowel diseases (e.g., inflammatory bowel disease and irritable bowel syndrome), cystic fibrosis, pregnancy, mental health problems, or medication.
A balanced diet, regular exercise, and reduced stress can help prevent constipation. In addition, a number of laxatives are clinically proven to provide effective relief from constipation. However, these treatments have been unsatisfactory as evidenced by new therapies. Thus, there is a need for an alternative treatment for constipation.
SUMMARY
This invention relates to compositions and methods for treating constipation.
In one aspect, this invention relates to a pharmaceutical composition, either in a dry form or a solublized from, containing a pharmaceutically acceptable enteric carrier and an anthracenedione compound of formula (I):
Figure US08466202-20130618-C00002
in which each of R1 and R2, independently, is H, C1-C6 alkyl, or C(O)Ra; each of R3, R5, R6, and R8, independently, is H, C1-C6 alkyl, or ORb; and each of R4 and R7, independently, is H, ORc, COORc, OC(O)ORd, SRd, NHRd, or C1-C6 alkyl optionally substituted with C3-C20 cycloalkyl, C1-C20 heterocycloalkyl, aryl, heteroaryl, ORc7 COORd, OC(O)ORd, SRd, or NHRd; in which each of Ra and Rc is C1-C10 alkyl; and each of Rb and Rd, independently, is H or C1-C10 alkyl.
The compounds described above include their pharmaceutically acceptable salts and their metal complexes. The salts can be formed, e.g., between a negatively charged oxygen in a compound and a positively charged inorganic or organic ion. The metal complexes can be formed, e.g., the oxygen atoms on the compounds coordinate with one or more metallic ions.
Referring to formula (I), a subset of the anthracenedione compounds described above are those in which each of R4 and R7, independently, is H, C1-C6 alkyl (e.g., CH3), or ORc (e.g., OCH3). In these compounds, each of R1, R2, R3, R5, R6, and R8 can be H. Exemplary anthracenedione compounds include chrysophanol and physcion:
Figure US08466202-20130618-C00003
The term “alkyl” refers to a saturated or unsaturated, linear or branched hydrocarbon moiety, such as —CH3, —CH2—CH═CH2, or branched —C3H7. The term “cycloalkyl” refers to a saturated or unsaturated, non-aromatic, cyclic hydrocarbon moiety, such as cyclohexyl or cyclohexen-3-yl. The term “heterocycloalkyl” refers to a saturated or unsaturated, non-aromatic, cyclic moiety having at least one ring heteroatom (e.g., N, O, or S), such as 4-tetrahydropyranyl or 4-pyranyl. The term “aryl” refers to a hydrocarbon moiety having one or more aromatic rings. Examples of aryl moieties include phenyl, phenylene, naphthyl, naphthylene, pyrenyl, anthryl, and phenanthryl. The term “heteroaryl” refers to a moiety having one or more aromatic rings that contain at least one heteroatom (e.g., N, O, or S). Examples of heteroaryl moieties include furyl, furylene, fluorenyl, pyrrolyl, thienyl, oxazolyl, imidazolyl, thiazolyl, pyridyl, pyrimidinyl, quinazolinyl, quinolyl, isoquinolyl, and indolyl.
Alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl mentioned herein include both substituted and unsubstituted moieties, unless specified otherwise. Possible substituents on cycloalkyl, heterocycloalkyl, aryl, and heteroaryl include, but are not limited to, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C8 cycloalkyl, C5-C8 cycloalkenyl, C3-C20 cycloalkyl, C1-C20 heterocycloalkyl, C1-C10 alkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, amino, C1-C10 alkylamino, C1-C20 dialkylamino, arylamino, diarylamino, hydroxyl, halogen, thio, C1-C10 alkylthio, arylthio, C1-C10 alkylsulfonyl, arylsulfonyl, acylamino, aminoacyl, aminothioacyl, amidino, guanidine, ureido, cyano, nitro, acyl, thioacyl, acyloxy, carboxyl, and carboxylic ester. On the other hand, possible substituents on alkyl include all of the above-recited substituents except C1-C10 alkyl, C2-C10 alkenyl, and C2-C10 alkynyl. Cycloalkyl, heterocycloalkyl, aryl, and heteroaryl can also be fused with each other.
The anthracenedione compounds described above can be used to treat constipation, i.e., improve intestinal motility while maintaining normal intestinal function. Increased intestinal motility shortens the duration for food to stay in the intestine. As a result, the intestine absorbs less food, which often includes carbohydrate, fat, cholesterol, low density lipoprotein, or triglyceride. Accordingly, the anthracenedione compounds allow a subject to decrease the body's intake of these nutrients and thereby (i) decrease cholesterol or triglycerides levels or (ii) reduce or maintain the body weight. Thus, this invention also relates to a method of using these compositions to improve intestinal motility and maintain normal intestinal function, to decrease cholesterol, low density lipoprotein, or triglycerides levels, and to reduce or maintain the body weight.
In yet another aspect, this invention relates to a method of treating inflammatory bowel disease or irritable bowel syndrome using the above-mentioned anthracenedione compounds.
Also within the scope of this invention are (1) use of the anthracenedione compounds described above in treating constipation, inflammatory bowel disease, or irritable bowel syndrome, improving intestinal motility and maintaining normal intestinal function, decreasing cholesterol, low density lipoprotein, or triglycerides levels, or reducing or maintaining the body weight; and (2) use of the anthracenedione compounds for the manufacture of a medicament or dietary supplement for the just-mentioned applications.
The details of one or more embodiments of the invention are set forth in the description below. Other features, objects, and advantages of the invention will be apparent from the description and the claims.
DETAILED DESCRIPTION
This invention is based, at least in part, on the unexpected discovery that two anthracenedione compounds, chrysophanol and physcion, found in Chinese herb Rheum palmatum Linne, are each effective in treating constipation. They do not have the side effects often seen in herb extracts prepared from the Rheum palmatum Linne, e.g., cramping, bloating, gas, and diarrhea. Further, each compound has a very low enteric absorption rate and therefore has minimal overall side effects to the body.
Accordingly, within the scope of this invention is a composition that contains an enteric carrier and one or more of the anthracenedione compounds described in the Summary section above. An enteric carrier is designed to minimize any fast release of a drug upon oral administration until the drug reaches the intestine. See, e.g., U.S. Pat. Nos. 5,188,836 and 6,306,434.
The composition can be a pharmaceutical composition that contains a pharmaceutically acceptable carrier or a dietary composition that contains a dietary suitable carrier. Preferably, an anthracenedione compound is added to the composition in pure form or substantially pure form. Anthracenedione compounds for use in this invention can be chemically synthesized or purified from herbs. For example, physcion and chrysophanol can be isolated from plants listed below in Tables A and B, respectively.
TABLE A
Physcion-containing Plants
Family Species
Lycopodiaceae Lycopodium japonicum Thunb.
Lycopodium obscurum L.
Urticaceae Boehmeria tricuspis (Hance) Makino
Polygonaceae Polygonum ciliinerve (Nakai) Ohwi
Polygonum cuspidatum Sieb. et Zucc.
Polygonum multiflorum Thunb.
Polygonum multiflorum Thunb.
Pteroxygonum giraldii Dammer et Diels
Rheum alexandrae Batal.
Rheum hotaoense C Y Cheng et T. C. Keo
Rheum likiangense Sam.
Rheum nobile Hook. f. et Thoms.
Rheum officinale Baill.
Rheum palmatum L.
Rheum palmatum L.
var. tanguticum Maxim. ex Regel
Rumex acetosa L.
Rumex chalepensis Mill.
Rumex dentatus L.
Rumex gmelini Turcz.
Rumex hastatus D. Don
Rumex japonicus Houtt.
Rumex nepalensis Spreng.
Rumex obtusifolius L.
Rumex patientia L.
Rumex patientia L.
subsp. tibeticus (Reich. f.) Reich. f.
Berberidaceae Dysosma majorensis (Gagnep.) Ying
Dysosma versipellis (Hance) M. Cheng ex Ying
Dysosma pleiantha (Hance) Woods.
Dysosma veitchii (Hemsl. et Wils.) Fu ex Ying
Lardizabalaceae Sargentodoxa cuneata (Oliv.) Rehd. et Wils.
Actinidiaceae Actinidia chinensis Planch.
Leguminosae Abrus cantoniensis Hance
Cassia angustifolia Vahl.
Cassia acutifolia Delile
Cassia nomame (Sieb.) Kitag.
Cassia abtusifolia L.
Cassia tora L.
Rhamnaceae Rhamnus cathartica L.
Rhamnus crenata Sieb. et Zucc.
Rhamnus frangula L.
Rhamnus napalensis (Wall.) Laws.
Sageretia thea (Osbeck) Johnst.
Ventilago leiocarpa Benth.
Rubhceae Morinda officinalis How.
Rubia cordifolia L.
Asteraceae Saussurea laniceps Hand.-Mazz.
Saussurea gnaphaloides (Royle) Sch.-Bip.
Saussurea medusa Maxim.
Saussurea tridactyla Sch.-Bip. Ex Hook. f.
Pandanaceae Pandanus tectorius Soland.
Orchidaceae Bletilla striata (Thumb.) Reichb. f.
TABLE B
Chrysophanol-containing Plants
Family Species
Taxaceae Amentotaxus argotaenia (Hance) Pilger.
Polygonaceae Polygonum cuspidatum Sieb. et Zucc.
Polygonum multiflorum Thunb.
Polygonum perfoliatum L.
Polygonum suffultum Maxim.
Rheum alexandrae Batal.
Rheum delavayi Franch.
Rheum emodi Wall.
Rheum franzenbachii Munt.
Rheum hotaoense C Y Cheng et T. C. Keo.
Rheum likiangense Sam.
Rheum nobile Hook. f. et Thoms.
Rheum officinale Baill.
Rheum palmatum L.
Rheum palmatum L.
var. tanguticum Maxim. ex Regel
Rumex acetosa L.
Rumex acetosa L.
Rumex chalepensis Mill.
Rumex crispus L.
Rumex dentatus L.
Rumex gmelini Turcz.
Rumex hastatus D. Don
Rumex japonicus Houtt.
Rumex nepalensis Spreng.
Rumex maritimus L.
Rumex obtusifolius L.
Rumex patientia L.
Rumex patientia L.
subsp. tibeticus (Reich. f.) Reich. f.
Lardizabalaceae Sargentodoxa cuneata (Oliv.) Rehd. et Wils.
Leguminosae Abrus cantoniensis Hance.
Cassia angustifolia Vahl.
Cassia acutifolia Delile
Cassia mimosoides L.
Cassia nomame (Sieb.) Kitag.
Cassia abtusifolia L.
Cassia tora L.
Cassia occidentalis L.
Simaroubaceae Brucea javanica (L.) Merr.
Rhamnaceae Rhamnus cathartica L.
Rhamnus crenata Sieb. et Zucc.
Rhamnus davurica Pall.
Rhamnus davurica Pall.
Rhamnus frangula L.
Umbelliferae Ligusticum chuanxiong Hort.
Acanthaceae Baphicacanthus cusia (Nees) Bremek.
Liliaceae Hemerocallis fulva (L.) L.
Hemerocallis lilio-asphodelus L.
Examples of a composition of the present invention include, but are not limited to, foods, food additives, nutritional supplements, and pharmaceutical preparations. It may be in the form of tablets, suspensions, implants, solutions, emulsions, capsules, powders, syrups, liquid compositions, ointments, lotions, creams, pastes, gels, or the like.
A dietary composition of this invention, either in a dry form or a solublized from, contains one or more of the anthrecenedione compounds and an edible carrier. Additional nutrients, such as minerals or amino acids, may be included. A dietary composition can also be a drink or food product. Examples of a drink product include, but are not limited to, tea-based beverages, juice, coffee, and milk. Examples of a food product include jelly, cookies, cereals, chocolates, snack bars, herbal extracts, dairy products (e.g., ice cream, and yoghurt), soy bean product (e.g., tofu), and rice products.
A pharmaceutical composition for oral administration can be any orally acceptable dosage form including capsules, tablets, emulsions and aqueous suspensions, dispersions, and solutions. In the case of tablets, commonly used carriers include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried corn starch. When aqueous suspensions or emulsions are administered orally, the active ingredient can be suspended or dissolved in an oily phase combined with emulsifying or suspending agents. If desired, certain sweetening, flavoring, or coloring agents can be added.
A composition of the present invention includes a carrier. Depending on the kind of the composition, a carrier may be a suitable dietary carrier or a pharmaceutically acceptable carrier. Examples of a pharmaceutically acceptable carrier include, but are not limited to, biocompatible vehicles, adjuvants, additives, and diluents to achieve a composition usable as a dosage form.
A “pharmaceutically acceptable carrier” refers to a carrier that, after administration to or upon a subject, does not cause undesirable physiological effects. The carrier in a pharmaceutical composition must be “acceptable” also in the sense that it is compatible with the active ingredient and, preferably, capable of stabilizing it. One or more solubilizing agents can be utilized as pharmaceutical carriers for delivery of an active anthracenedione compound. Examples of other carriers include colloidal silicon oxide, magnesium stearate, cellulose, sodium lauryl sulfate, and D&C Yellow #10.
The above-described composition, in any of the forms described above, can be used for treating constipation. In fact, as shown in the examples below, the composition increased the production of feces and feces water content in a subject without causing side effects such as diarrhea. Also, it was effective in reducing or maintaining the body weight of the subject.
The term “treating” refers to administering an effective amount an anthrecenedione compound to a subject that has a disorder, e.g., constipation, inflammatory bowel disease, or irritable bowel syndrome, or has a symptom of such a disorder, or has a predisposition toward such a disorder, with the purpose to cure, heal, alleviate, relieve, alter, remedy, ameliorate, improve, or affect the disorder, the symptoms of the disorder, or the predisposition toward the disorder. The term “administration” covers oral delivery to a subject a composition of the invention in any suitable form, e.g., food product, beverage, tablet, capsule, suspension, and solution. An “effective amount” refers to a dose of the composition that is sufficient to provide a physical benefit (e.g., increasing feces production and reducing the body weight) or a therapeutic benefit (e.g., lowering cholesterol levels). Both in vivo and in vitro studies can be conducted to determine optimal administration routes and doses. Increasing feces production refers to an increase in the wet weight of feces produced by a subject by 15% or more one day after the subject receives an active composition as determined by the method described in Example 3 below or any analogous method.
A composition of the present invention may be used alone or in combination with other biologically active ingredients. It may be administered to a subject in a single dose or multiple doses over a period of time, generally by oral administration. Various administration patterns will be apparent to those skilled in the art. The dosage ranges for the administration of the composition are those large enough to produce the desired effect. The dosage should not be so large as to cause any adverse side effects, such as unwanted cross-reactions and the like. Generally, the dosage will vary with the age, weight, sex, condition, and extent of a condition in a subject, and the intended purpose. The dosage can be determined by one of skill in the art without undue experimentation. The dosage can be adjusted in the event of any counter indications, tolerance, or similar conditions. Those of skill in the art can readily evaluate such factors and, based on this information, determine the particular effective concentration of a composition of the present invention to be used for an intended purpose.
The specific examples below are to be construed as merely illustrative, and not limitative of the remainder of the disclosure in any way whatsoever. Without further elaboration, it is believed that one skilled in the art can, based on the description herein, utilize the present invention to its fullest extent. All publications cited herein are hereby incorporated by reference in their entirety.
Example 1
Aloe-emodin, rhein, emodin, chrysophanol, and physcion were isolated from a Rheum palmatum Linne extract STD-05. To prepare STD05, 3.2 kg Rheum palmatum was extracted with 12 L of ethyl acetate for 18 hours twice. The resulting solution was filtered through a 200 mesh filter. The filtrate was concentrated under vacuum, dissolved in 2 L of 95% ethanol, and precipitated with 6 L of water. The precipitant was then dissolved in 95% ethanol and precipitated again with water to generate “Fr-I” precipitant. The supernatant was fractionated in a Diaion HP-20 column and eluted with 30% ethanol, followed by 95% ethanol and ethyl acetate. Elutes fractionated from 95% ethanol (Fr-D) and from ethyl acetate (Fr-E) were combined with Fr-I as STD05. Twenty grams of STD05 was dissolved in ethyl acetate and mixed with a small amount of silica gel. Ethyl acetate was then removed under vacuum to give a mixture. The mixture was purified on a silica gel column eluting with 0% to 5% ethyl acetate in hexanes. Fractions thus obtained were analyzed by HPLC. Five compounds were detected by HPLC. Fractions of each compound were combined, respectively. The solvent of each combined solution was removed under vacuum to give five solid products. The solid products were recrystallized from acetone to give 220 mg of aloe-emodin, 290 mg of rhein, 1270 mg of emodin, 2220 mg of chrysophanol, and 790 mg of physcion. The results are summarized in Table 1 below:
TABLE 1
Compound Isolation
Eluent Yield (%)
Hexanes:Ethyl Weight From the From
Compounds Acetate (mg) extract the herb
Aloe-emodin 20:1 220 1.10 0.012
Rhein 20:1 290 1.45 0.016
Emodin 40:1 1270 6.35 0.071
Chrysophanol 180:1  2220 11.10 0.125
Physcion 160:1  790 3.95 0.044
Each of the isolated compounds was crystallized and examined under a microscope.
Example 2
The laxative activities by Rheum palmatum Linne extracts were studied. A crude Rheum palmatum Linne extract and STD05 were obtained from SunTen Phytotech Co., Ltd. (Jhonghe City, Taiwan). Commercial available laxatives, Through® (Chung Mei Pharmaceutical Co., Ltd.; active ingredient: Sennosides 20 mg, as Sennosides A+B 12 mg, Lot. 009A 051) and Dulcolax® (Boehringer Ingelheim, Taiwan, Ltd.; active ingredient: Bisacodyl; Lot. 480-4942) were obtained from a pharmacy.
Forty-two healthy male S.D. rats (8 weeks old; National Laboratory Animal Center, Taiwan) were divided into seven groups (six in each) and tested for the laxative activity by Rheum palmatum Linne extracts. The rats in one group were not fed with any extract or drug and used as negative controls. The rats in the second and third group were given Sennosides (3.55 mg/kg) and Bisacodyl (1.75 mg/kg), respectively, and used as positive controls. The Rats in the other four groups were given Rheum palmatum Linne crude extract (500 mg/kg), filtered crude extract STD03 (180 mg/kg), and STD05 (STD05-1: 12 mg/kg and STD05-2: 24 mg/kg), respectively. All substances were administered orally everyday for three weeks.
The experiments were carried out under conditions in which temperature, humidity, and lighting were all controlled. Each rat was fed standard rat food and water ad libitum in housing that provided a 12-hour light/dark cycle. The rats were divided into seven groups according to the body weights.
The first part of the experiment studied the effect of the above-mentioned extracts on feces production. During the three-week period, any rat that appeared dying was euthanized, dissected, and studied to check for any illness or injures. Any complications or illness were analyzed by H&E stains to determine the cause of death and to allow for dosage reconsiderations for future experiments.
During this period, the body weights of the rats were weighed each day and recorded. Feces of each rat were studied three times during the period for any unusual observations. Specifically, the amounts of feces were weighed on Days 11, 15, 18, and 21. During observation, each rat was placed in a metabolic cage. Feces were collected every twenty-four hours. The number of collected feces pellets was counted, and the pellets' shapes and colors were evaluated. After weighing the moist feces, they were dried in an oven at 100° C. for twenty-four hours. The water content from the feces was calculated according to the following formula:
Water content percentage=[(wet weight−dry weight)/wet weight]×100%.  (I)
The results are summarized in Table 2 below:
TABLE 2
Effects of Rheum palmatum Linne extracts on feces production
Rheum
Control palmatum Bisacodyl Sennosides STD03 STD05-1 STD05-2
Day 11 Wet Weight (g) 21.66 39.46 33.84 29.21 27.60 22.79 22.59
Pellet count 87 178 116 121 126 105 116
Water content (%) 48.82 56.92 64.45 52.70 53.35 50.19 42.07
Day 15 Wet Weight (g) 16.86 28.50 41.64 30.95 36.86 27.34 29.09
Pellet count 84 139 110 119 153 130 124
Water content (%) 42.89 49.53 68.34 60.40 57.19 47.57 48.83
Day 18 Wet Weight (g) 22.14 24.98 30.14 23.90 25.01 24.51 29.48
Pellet count 90 126 81 106 124 114 123
Water content (%) 43.83 48.36 66.65 47.30 49.40 47.63 50.19
Day 21 Wet Weight (g) 22.79 36.52 40.13 27.80 24.18 24.51 27.17
Pellet count 91 105.6 108 123 115 97 108
Water content (%) 47.85 63.89 68.02 44.73 47.56 51.10 43.54
After the above-discussed feces tests, intestinal motility tests were conducted. Before the experiment, the rats were fasted for at least sixteen hours. The rats were then given the aforementioned drugs or extracts. After 3 hours, each rat was given 3 ml/kg of 0.5% methylcellulose solution-0.5% Evans blue dye. Each rat was sacrificed 30 minutes later and its abdominal cavity was cut open. The entire small intestine was extracted and carefully straightened. The entire stretch between the pylorous and cecum was measured as the small intestine length. The distance traveled by Evans blue dye along the intestines was also measured. During dissection, any unusual observations were recorded and photographed. The intestinal motility function was calculated in the following formula:
Intestine motility=(Evans blue dye length/small intestine length)×100%.  (II)
The results are summarized in Table 3 below.
TABLE 3
Effects of Rheum palmatum Linne extracts on intestine motility.
STD03 STD05-1 STD05-2
Small intestine Dye length Intestinal Small intestine Dye length Intestinal Small intestine Dye length Intestinal
length (cm) (cm) motility (%) length (cm) (cm) motility (%) length (cm) (cm) motility (%)
105 83.5 79.5 101 77.5 76.7 117 83.5 71.4
118.5 75 63.3 102.5 72.5 70.7 114 89 78.1
111 80.5 72.5 113.5 105 92.5 112 99.5 88.8
110 79 71.8 107 70 65.4 107 89 83.2
120 87 72.5 110 86 78.2 101 86 85.1
108 77.5 71.8 118.5 81 68.4
Mean 71.9 Mean 75.9 Mean 79.2
SD 5.8 SD 9.3 SD 8.1
Intestine motility data were expressed as mean±SD. Data were analyzed using the one-way ANOVA method. For comparison within the groups, a Post hoc Comparison was applied. In both feces production and intestine motility analyses, p<0.05 indicates significant differences. For the feces production tests, the data for each group and each time point represent the total wet weight or pellet count of the six rats in the group.
Example 3
The aforementioned STD05 and compounds were studied for the laxative activity. Healthy male S.D. rats (BioLASCO Taiwan Co. Ltd.) were divided into three groups (i.e., Groups 1-3) in this study.
In Group I, 6 rats, as negative control, were given no treatment; 6 rats, as positive control, were given 3.35 mg/kg/day Sennosides (Through®, Chung Mei Pharmaceutical Co., Ltd; Active ingredient: Sennosides 20 mg, as sennoside A+B 12 mg, Lot. 012F 006); 6 rats were treated STD05 (8 mg/kg/day); 6 rats were treated with an extract fraction containing aloe-emodin, rhein, and emodin (“ARE”, 8 mg/kg/day); 6 rats were treated with Aloe-emodin (4 mg/kg/day); and 6 rats were treated with Rhein (4 mg/kg/day).
In Group II, 6 rats, as negative control, were given no treatment; 6 rats, as positive control, were given 3.35 mg/kg/day Sennosides; 6 rats were treated STD05 (24 mg/kg/day); 6 rats were treated with an extract fraction containing ARE (24 mg/kg/day); 6 rats were treated with Chrysophanol (4 mg/kg/day); and 6 rats were treated with Emodin (4 mg/kg/day).
In Group III, 6 rats, as negative control, were given no treatment; 6 rats were treated with Physcoin (4 mg/kg/day); and 6 rats were treated with a mixture of chrysophanol and physcion (8 mg/kg/day, “CP”).
The experiments were carried out under controlled temperature, humidity, and lighting. Each rat was fed standard rat food and water ad libitum in housing that provided a 12-hour light/dark cycle. For statistical comparison, all of the rats were divided into six sets according to the body weights.
The first part of the experiment studied the effect of the test substances on feces production. During the 10-day period, the body weights of the rats were weighed each day and recorded. The rat's feces was also studied three times in the manner described above during the 10-day period for any unusual observations. During the 10-day period, any rat that appeared dying was euthanized, dissected, and examined for any illness or injury. Any complications or illness were analyzed by H&E stains to determine the cause of death and to allow for dosage reconsiderations for future experiments. Summarized in Table 4 below are the effects of the compounds, mixtures, or extracts on the rat body weights.
TABLE 4
Effects of compounds and Rheum palmatum Linne extracts on body weight
Group I Group II Group III
Control Control Control
Start End Start End Start End
Day 1 Day 10 Difference Day 1 Day 10 Difference Day 1 Day 10 Difference
280 335 55 355 400 45 415 450 35
285 345 60 365 405 40 430 460 30
290 355 65 365 410 45 435 470 35
275 330 55 345 385 40 405 440 35
285 345 60 360 410 50 425 460 35
295 355 60 380 435 55 450 475 25
Mean 285 344 59 362 408 46 427 459 33
SD 7 10 4 12 16 6 16 13 4
Sennosides Sennosides
Start End Start End Start End
Day 1 Day 10 Difference Day 1 Day 10 Difference Day 1 Day 10 Difference
280 325 45 340 370 30
285 330 45 350 395 45
290 350 60 365 405 40
275 310 35 325 360 35
285 350 65 370 410 40
295 365 70 390 445 55
Mean 285 338 53 357 398 41
SD 8 20 14 23 30 9
STD05(8 mg/kg) STD05 (24 mg/kg)
Start End Start End Start End
Day 1 Day 10 Difference Day 1 Day 10 Difference Day 1 Day 10 Difference
275 330 55 345 380 35
285 345 60 355 385 30
290 350 55 360 395 35
275 335 60
285 345 60
295 355 65 375 395 20
Mean 285 343 59 359 389 30
SD 7 15 4 13 8 7
ARE (8 mg/kg) ARE (24 mg/kg)
Start End Start End Start End
Day 1 Day 10 Difference Day 1 Day 10 Difference Day 1 Day 10 Difference
270 325 55 335 370 35
285 345 60 360 405 45
295 350 55 370 405 35
280 325 45 335 370 35
285 345 60 355 395 40
290 365 75 375 435 60
Mean 284 343 58 355 397 42
SD 9 15 10 17 25 10
Aloe-emodin (4 mg/kg) Chrysophanol (4 mg/kg) Physcion (4 mg/kg)
Start End Start End Start End
Day 1 Day 10 Difference Day 1 Day 10 Difference Day 1 Day 10 Difference
270 315 45 330 370 40 385 410 25
285 335 50 350 370 20 400 430 30
295 345 50 355 385 30 405 450 45
275 315 40 325 350 25 365 385 20
285 325 40 340 370 30 385 415 30
290 345 55 360 410 50 430 460 30
Mean 283 330 58 343 376 33 395 425 30
SD 9 14 10 14 20 11 22 28 8
Rhein (4 mg/kg) Emodin (4 mg/kg) CP (8 mg/kg)
Start End Start End Start End
Day 1 Day 10 Difference Day 1 Day 10 Difference Day 1 Day 10 Difference
275 330 55 340 370 30 390 415 25
280 330 50 345 380 35 395 420 25
285 340 55 360 405 45 430 455 25
275 310 35 330 340 10 360 385 25
280 335 55 350 385 35 405 435 30
285 340 55 360 395 35 405 440 35
Mean 280 331 51 348 379 32 398 425 28
SD 4 11 8 12 23 12 23 24 4
As shown in Table 4, STD05 and the compounds are effective in maintaining the body weight. It was unexpected that pure form of each compound was also effective.
During the period, feces produced by the rats were studied days 1, 5, and 10 in the same manner described above. It was found that STD05 promoted feces production. In the 10-day period, the rats administered with STD05 produced more feces (wet weight) that the rats in the control group by about 32%. In addition, the pellet counts for the rats administered with STD05 were greater than those for the control rats by about 20%. Furthermore, STD05 increased the water content in feces by about 18%. The same experiments were conducted on rats administered with physcion, aloe-emodin, chrysophanol, rhein, emodin, CP, and ARE. The results are summarized in Table 5 below:
TABLE 5
Effects of compounds and extracts on feces production
Sennosides STD05 ARE Aloe-emodin Rhein
Group I Control (3.35 mg/kg) (8 mg/kg) (8 mg/kg) (4 mg/kg) (4 mg/kg)
Day 1 Wet Weight (g) 13.42 18.72 14.06 9.43 17.00 17.57
Pellet count 85 101 79 63 98 102
Water content (%) 32.59 45.69 39.73 32.54 42.48 42.58
Day 5 Wet Weight (g) 18.48 26.16 27.76 18.53 20.21 16.88
Pellet count 90 119 119 82 104 89
Water content (%) 39.83 48.68 48.44 47.35 41.98 44.55
Day 10 Wet Weight (g) 24.15 36.38 33.83 19.87 28.86 23.52
Pellet count 93 146 125 89 125 119
Water content (%) 49.11 57.4 54.55 48.36 50.48 46.53
Sennosides STD05 ARE Chrysophanol Emodin
Group II Control (3.35 mg/kg) (24 mg/kg) (24 mg/kg) (24 mg/kg) (4 mg/kg)
Day 1 Wet Weight (g) 24.15 36.19 37.27 17.62 28.86 16.86
Pellet count 99 134 125 67 128 90
Water content (%) 51.11 61.09 60.65 50.21 50.82 42.38
Day 5 Wet Weight (g) 22.85 36.42 27.28 18.60 26.48 25.51
Pellet count 94 118 109 79 119 112
Water content (%) 49.70 61.53 55.47 50.73 51.22 51.00
Day 10 Wet Weight (g) 25.29 36.21 31.07 25.66 28.83 26.21
Pellet count 84 132 101 107 127 106
Water content (%) 48.64 53.99 62.19 53.35 56.52 53.64
Physcion CP
Group III Control (4 mg/kg) (8 mg/kg)
Day 1 Wet Weight (g) 18.32 35.38 28.74
Pellet count 65 134 115
Water content (%) 49.51 55.73 52.82
Day 5 Wet Weight (g) 22.41 35.17 31.26
Pellet count 78 128 112
Water content (%) 50.93 53.80 56.36
Day 10 Wet Weight (g) 22.37 29.43 26.37
Pellet count 91 121 106
Water content (%) 47.09 47.66 50.93
As shown in Table 5, during the 10-day period, except ARE, all compounds promoted feces production in the order of physcion>CP>aloe-emodin>chrysophanol>rhein>emodin (from the most potent to the least potent). For example, physcion, CP, aloe-emodin, chrysophanol, rhein, and emodin increased the feces amount (wet weight) by 93%, 57%, 27%, 19%, 31%, and −30%, respectively, at Day 1; by 57%, 39%, 9%, 16%, −9%, and 12%, respectively, at Day 5; and by 32%, 18%, 20%, 14%, −1%, and 4%, respectively, at Day 10. The averages are 61%, 38%, 19%, 16%, 7%, and −5%, respectively.
After finishing the feces tests, intestinal motility tests were conducted in the same manner described above. During dissection, any unusual observations were recorded and photographed. For comparison within the groups, a Post hoc Comparison was applied with p<0.05 indicating significant differences. It was found that the rat received STD05 (containing Physcion and Chrysophanol) and Sennosides had greater intestinal motility (69.3% and 67.9%) than the control rats (61.1%).
Example 4
STD05 was tested in Guinea pig ileum electrical stimulation increase tissue assay at test concentrations ranging from 10 nm to 10 μM by MDS Pharma Services. The assay was conducted according to the method described in Moritoki, et al., “Effects of methylxanthines and imidazole on the contraction of guinea pig ileum induced by transmural simulation” Eur. J. Pharmacol. 35, 185-198.
The results show that STD05 increased neurogenic twitch by 36% at the concentrations of 0.03 and 0.3 μM and caused reduction in the post-treatment basal twitch response of −24% at the concentration of 10 μM.
Example 5
STD05 was evaluated for possible hypocholesterolemic activity in hamsters fed with a high cholesterol diet. STD05 at 30 and 100 mg/kg was administered orally once a day for 14 consecutive days. Blood was drawn from overnight fasted hamsters on day 1 (pre-treatment), day 8 (7 days post dosing), and day 15 (14 days post dosing) to measure serum total cholesterol, high density lipoprotein, low density lipotprotein and triglyceride levels. Post-treatment values on day 8 and day 15 were expressed in percentage of respective pretreatment values (day) in order to assess lipid-lowering effect of the tested composition. Decrease of 20% or more in total cholesterol or low density lipoprotein or increase of 20% or more in high density lipoprotein as well as decrease of 40% or more in triglyceride relative to the vehicle group were considered significant. Also one-way ANOVA followed by Dunnet's test was applied for statistical comparison between the vehicle and treated groups.
The results show that STD05 at the concentration of 100 mg/kg had significant low-density lipoprotein lowering effect. The effect became evident after the two week treatment.
Other Embodiments
All of the features disclosed in this specification may be combined in any combination. Each feature disclosed in this specification may be replaced by an alternative feature serving the same, equivalent, or similar purpose. Thus, unless expressly stated otherwise, each feature disclosed is only an example of a generic series of equivalent or similar features.
From the above description, one skilled in the art can easily ascertain the essential characteristics of the present invention, and without departing from the spirit and scope thereof, can make various changes and modifications of the invention to adapt it to various usages and conditions. Thus, other embodiments are also within the scope of the following claims.

Claims (14)

What is claimed is:
1. A method of treating an inflammatory bowel disease in a subject, comprising administering to the subject in need thereof an effective amount of a purified chrysophanol.
2. The method of claim 1, wherein the inflammatory bowel disease is Crohn's disease or ulcerative colitis.
3. The method of claim 1, wherein said compound is administered in a composition comprising a pharmaceutically acceptable carrier.
4. The method of claim 3, wherein the pharmaceutically acceptable carrier is an enteric carrier.
5. The method of claim 1, wherein said compound is administered in a form of a dietary composition.
6. A method of treating irritable bowel syndrome in a subject, comprising administering to the subject in need thereof an effective amount of a purified compound of physcion or chrysophanol.
7. The method of claim 6, wherein said compound is physcion.
8. The method of claim 7, wherein said compound is administered in a composition comprising a pharmaceutically acceptable carrier.
9. The method of claim 8, wherein the pharmaceutically acceptable carrier is an enteric carrier.
10. The method of claim 6, wherein said compound is administered in a form of a dietary composition.
11. The method of claim 6, wherein said compound is chrysophanol.
12. The method of claim 11, wherein said compound is administered in a composition comprising a pharmaceutically acceptable carrier.
13. The method of claim 12, wherein the pharmaceutically acceptable carrier is an enteric carrier.
14. The method of claim 11, wherein said compound is administered in a form of a dietary composition.
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Publication number Priority date Publication date Assignee Title
BRPI0709472A2 (en) * 2006-04-07 2011-07-12 Sunten Phytotech Co Ltd "pharmaceutical composition, dietary composition and composition use
DE102008035285A1 (en) * 2008-07-02 2010-01-07 Hermann-Josef Wilhelm Extraction of active substances from group of anthraquinone and phenols and/or polyphenols from a plant, where new plant variety Igniscum (CPVO 2007/0149) or Candy (CPVO 2007/1958) registered to variety protection is requisitioned as plant
CN104569259B (en) * 2014-12-30 2016-05-18 广州白云山汉方现代药业有限公司 The clear the snow assay method of scopolactone in lotus bolt, umbelliferone and Content of Osthole of a kind of woman
US9801898B2 (en) 2015-02-06 2017-10-31 Emory University Glutamate dehydrogenase 1 inhibitors and methods of treating cancer
JP7084930B2 (en) * 2017-01-18 2022-06-15 タイレックス， インコーポレーテッド Compositions for use in treating inflammatory bowel disease and intestinal colitis

Citations (28)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3881000A (en) 1971-09-08 1975-04-29 Mundipharma Ag Bis-(phosphorylated anthralin) compounds in the treatment of psoriasis and arthritis
JPS59157008A (en) 1983-02-28 1984-09-06 Sumitomo Chem Co Ltd Fungicide containing organic solvent extract of seed and pod of senna as active component
WO1990008759A1 (en) 1989-01-27 1990-08-09 Sloan-Kettering Institute For Cancer Research Derivatives of chrysophanol
US5053431A (en) 1989-01-27 1991-10-01 Sloan-Kettering Institute For Cancer Research Derivatives of chrysophanol as topoisomerase II inhibitors
US5316768A (en) 1990-12-28 1994-05-31 Murdock International Corporation Pharmaceutical compositions having antiviral activity against human cytomegalovirus
US5476952A (en) 1993-03-12 1995-12-19 Sloan-Kettering Institute For Cancer Research Antitumor cyclopentnaphthoquinone and cyclopentanthraquinone derivatives
EP0705601A1 (en) 1994-10-04 1996-04-10 LOMAPHARM Rudolf Lohmann GmbH KG Pharmazeutische Fabrik Anthraquinones containing solutions for parenteral administration
US5648258A (en) 1992-10-22 1997-07-15 Bio-Technical Resources Anthraquinone inhibition of methane production in a ruminant animal
WO1997027848A1 (en) 1996-01-31 1997-08-07 Board Of Regents, The University Of Texas System SENSITIZATION OF HER2/neu OVER-EXPRESSING CANCER CELLS TO CHEMOTHERAPEUTIC DRUGS
CN1222358A (en) 1997-07-08 1999-07-14 胡团敏 Sanhuang enema liquid
US6187313B1 (en) 1996-03-26 2001-02-13 Nature's Sunshine Products, Inc. Composition and method for treating and preventing helicobactor-pylori-associated stomach gastritis, ulcers and cancer
WO2001049281A2 (en) 1999-12-30 2001-07-12 Proteotech, Inc. POLYHYDROXYLATED AROMATIC COMPOUNDS FOR THE TREATMENT OF AMYLOIDOSIS AND α-SYNUCLEIN FIBRIL DISEASES
CN1319747A (en) 2001-03-11 2001-10-31 刘起麟 Method for use of crystallized essence box in filter net of air conditioner
US20020164387A1 (en) 2001-02-12 2002-11-07 Kaiyuan Wei Herbal composition and method for controlling body weight and composition
CN1440747A (en) 2003-03-31 2003-09-10 中国人民解放军肾脏病研究所 Application of chrysophanic acid and chrysophanate in preparing obesity treating medicine
WO2003089577A2 (en) 2002-04-15 2003-10-30 Michigan State University Antihelminthic anthraquinones and method of use thereof
WO2003089576A2 (en) 2002-04-15 2003-10-30 Michigan State University Anticancer anthraquinones and method of use thereof
JP2004083436A (en) 2002-08-23 2004-03-18 Minofuaagen Seiyaku:Kk Astrocyte activation inhibitor and prophylactic or therapeutic agent for organ fibrosis
US20040071799A1 (en) 2001-02-12 2004-04-15 Xiurong Xu Herbal compositions and methods for effecting weight loss in humans
US20040121968A1 (en) 2002-12-23 2004-06-24 Alexander Ljubimov Antiangiogenesis by inhibiting protein kinase CK2 activity
WO2004052294A2 (en) 2002-12-06 2004-06-24 Board Of Regents, The University Of Texas System Compositions and methods related to lipid:emodin formulations
CN1511518A (en) 2002-12-30 2004-07-14 北京大学第一医院 Use of chrysophanic acid in inhibiting vascularization
DE10305768A1 (en) 2003-02-11 2004-08-19 Justus-Liebig-Universität Giessen Selective staining of lipophilic cells or components, useful particularly in diagnostic determination of eosinophils, uses an extract containing physcion and fluorescent microscopy
GB2398779A (en) 2003-02-26 2004-09-01 Arakis Ltd 1,8-dihydroxyanthraquinone-6-carboxamide derivatives as modulators of IL-10 production for treatment of autoimmune or inflammatory conditions
KR20050001556A (en) 2003-06-25 2005-01-07 서왕식 The composition of materials to prevent the adult disease and reduce the obesity
WO2005051361A1 (en) 2003-11-19 2005-06-09 Inkine Pharmaceutical Company, Inc. Colonic purgative composition with soluble binding agent
WO2007064691A1 (en) * 2005-12-02 2007-06-07 Nabil Habib Lab Treatment of cancer and other diseases
US7767719B2 (en) 2006-04-07 2010-08-03 Sunten Phytotech Co., Ltd. Anthracenedione compounds

Family Cites Families (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6306434B1 (en) * 1997-02-12 2001-10-23 Chong Kun Dang Corp. Pharmaceutical composition comprising cyclosporin solid-state microemulsion
RU2264223C2 (en) * 2000-10-23 2005-11-20 Открытое Акционерное Общество "Фармацевтическая Фабрика Санкт-Петербурга" Dry laxative mixture, purgative agent, preparative form of dry laxative mixture and method for preparing laxative mixture
CN1319393A (en) * 2001-02-28 2001-10-31 中国人民解放军肾脏病研究所 Application of chrysophanic acid in curing hyperlipemia
RU2215424C2 (en) * 2001-11-30 2003-11-10 Казаченко Александра Геннадьевна Phytotea for clearance of organism and reduction of weight
RU2200023C1 (en) * 2002-04-18 2003-03-10 Ныркова Людмила Ефимовна Preparation eliciting immunomodulating activity
RU2259839C2 (en) * 2003-11-12 2005-09-10 Закрытое акционерное общество "МАГИ-ФАРМА" "nepolnita-phyto" tea out of medicinal plants for reducing excessive body weight
RU2244555C1 (en) * 2004-02-04 2005-01-20 Ныркова Людмила Ефимовна Preparation eliciting with immunomodulating activity

Patent Citations (40)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3881000A (en) 1971-09-08 1975-04-29 Mundipharma Ag Bis-(phosphorylated anthralin) compounds in the treatment of psoriasis and arthritis
JPS59157008A (en) 1983-02-28 1984-09-06 Sumitomo Chem Co Ltd Fungicide containing organic solvent extract of seed and pod of senna as active component
WO1990008759A1 (en) 1989-01-27 1990-08-09 Sloan-Kettering Institute For Cancer Research Derivatives of chrysophanol
US4966918A (en) 1989-01-27 1990-10-30 Sloan-Kettering Institute For Cancer Research Derivatives of chryosphanol
US5053431A (en) 1989-01-27 1991-10-01 Sloan-Kettering Institute For Cancer Research Derivatives of chrysophanol as topoisomerase II inhibitors
US5316768A (en) 1990-12-28 1994-05-31 Murdock International Corporation Pharmaceutical compositions having antiviral activity against human cytomegalovirus
US5648258A (en) 1992-10-22 1997-07-15 Bio-Technical Resources Anthraquinone inhibition of methane production in a ruminant animal
US5476952A (en) 1993-03-12 1995-12-19 Sloan-Kettering Institute For Cancer Research Antitumor cyclopentnaphthoquinone and cyclopentanthraquinone derivatives
EP0705601A1 (en) 1994-10-04 1996-04-10 LOMAPHARM Rudolf Lohmann GmbH KG Pharmazeutische Fabrik Anthraquinones containing solutions for parenteral administration
WO1997027848A1 (en) 1996-01-31 1997-08-07 Board Of Regents, The University Of Texas System SENSITIZATION OF HER2/neu OVER-EXPRESSING CANCER CELLS TO CHEMOTHERAPEUTIC DRUGS
US6187313B1 (en) 1996-03-26 2001-02-13 Nature's Sunshine Products, Inc. Composition and method for treating and preventing helicobactor-pylori-associated stomach gastritis, ulcers and cancer
CN1222358A (en) 1997-07-08 1999-07-14 胡团敏 Sanhuang enema liquid
WO2001049281A2 (en) 1999-12-30 2001-07-12 Proteotech, Inc. POLYHYDROXYLATED AROMATIC COMPOUNDS FOR THE TREATMENT OF AMYLOIDOSIS AND α-SYNUCLEIN FIBRIL DISEASES
US20010047032A1 (en) 1999-12-30 2001-11-29 Castillo Gerardo M. Polyhydroxylated aromatic compounds for the treatment of amyloidosis and alpha-synuclein fibril diseases
US20040152760A1 (en) 1999-12-30 2004-08-05 Castillo Gerardo M. Polyhydroxylated aromatic compounds for the treatment of amyloidosis and alpha-synuclein fibril diseases
US20040071799A1 (en) 2001-02-12 2004-04-15 Xiurong Xu Herbal compositions and methods for effecting weight loss in humans
US20020164387A1 (en) 2001-02-12 2002-11-07 Kaiyuan Wei Herbal composition and method for controlling body weight and composition
CN1319747A (en) 2001-03-11 2001-10-31 刘起麟 Method for use of crystallized essence box in filter net of air conditioner
US6800615B2 (en) 2002-04-15 2004-10-05 Board Of Trustees Of Michigan State University Antihelminthic anthraquinones and method of use thereof
WO2003089576A2 (en) 2002-04-15 2003-10-30 Michigan State University Anticancer anthraquinones and method of use thereof
US20040106686A1 (en) 2002-04-15 2004-06-03 Board Of Trustees Of Michigan State University Antihelminthic anthraquinones and method of use thereof
US20040116361A1 (en) 2002-04-15 2004-06-17 Board Of Trustees Of Michigan State University Antihelminthic anthraquinones and method of use thereof
US20030229032A1 (en) 2002-04-15 2003-12-11 Board Of Trustees Of Michigan State University Antihelminthic anthraquinones and method of use thereof
US7132403B2 (en) 2002-04-15 2006-11-07 Board Of Trustees Of Michigan State University Antihelminthic anthraquinones and method of use thereof
WO2003089577A2 (en) 2002-04-15 2003-10-30 Michigan State University Antihelminthic anthraquinones and method of use thereof
US6903076B2 (en) 2002-04-15 2005-06-07 Board Of Trustees Of Michigan State University Antihelminthic anthraquinones and method of use thereof
US6875746B1 (en) 2002-04-15 2005-04-05 Board Of Trustees Of Michigan State University Anticancer anthraquinones and method of use thereof
JP2004083436A (en) 2002-08-23 2004-03-18 Minofuaagen Seiyaku:Kk Astrocyte activation inhibitor and prophylactic or therapeutic agent for organ fibrosis
US20050008664A1 (en) 2002-12-06 2005-01-13 Board Of Regents, The University Of Texas System Compositions and methods related to lipid:emodin formulations
WO2004052294A2 (en) 2002-12-06 2004-06-24 Board Of Regents, The University Of Texas System Compositions and methods related to lipid:emodin formulations
US20040121968A1 (en) 2002-12-23 2004-06-24 Alexander Ljubimov Antiangiogenesis by inhibiting protein kinase CK2 activity
CN1511518A (en) 2002-12-30 2004-07-14 北京大学第一医院 Use of chrysophanic acid in inhibiting vascularization
DE10305768A1 (en) 2003-02-11 2004-08-19 Justus-Liebig-Universität Giessen Selective staining of lipophilic cells or components, useful particularly in diagnostic determination of eosinophils, uses an extract containing physcion and fluorescent microscopy
GB2398779A (en) 2003-02-26 2004-09-01 Arakis Ltd 1,8-dihydroxyanthraquinone-6-carboxamide derivatives as modulators of IL-10 production for treatment of autoimmune or inflammatory conditions
CN1440747A (en) 2003-03-31 2003-09-10 中国人民解放军肾脏病研究所 Application of chrysophanic acid and chrysophanate in preparing obesity treating medicine
KR20050001556A (en) 2003-06-25 2005-01-07 서왕식 The composition of materials to prevent the adult disease and reduce the obesity
WO2005051361A1 (en) 2003-11-19 2005-06-09 Inkine Pharmaceutical Company, Inc. Colonic purgative composition with soluble binding agent
US20050129781A1 (en) 2003-11-19 2005-06-16 Stephen Skiendzielewski Colonic purgative composition with soluble binding agent
WO2007064691A1 (en) * 2005-12-02 2007-06-07 Nabil Habib Lab Treatment of cancer and other diseases
US7767719B2 (en) 2006-04-07 2010-08-03 Sunten Phytotech Co., Ltd. Anthracenedione compounds

Non-Patent Citations (12)

* Cited by examiner, † Cited by third party
Title
About.com. Alternative Medicine, Rhubarb. Mar. 30, 2006.
Farr, et al., "Therapy for Chronic Constipation with Plant Laxatives", Modern Medicine, vol. 19, pp. 54-60, May 19, 2002.
International Search Report and Written Opinion issued for Application No. PCT/US07/66224, dated Aug. 25, 2008, 12 pages.
Manganiotis et al.: "Urologic Complications of Crohn's Disease". Crohn's Disease, vol. 81, No. 1, Feb. 2001.
Manganiotis, Angelos N. MD, et al., "Urologic Complications of Crohn's Disease", Surgical Clinics of North America, vol. 81, No. 1, Feb. 2001, pp. 197-215.
Nicolaus, B.J.R., "Symbiotic Approach to Drug Design", Decision Making on Drug Research, Jan. 1, 1983, pp. 173-186.
Okamato, et al., Digestive Diseases and Sciences, Oct. 2005, vol. 50, Supplement 1, pp. S34-S38.
Papagergiou et al., "Study on the Antibiotic Fraction of Alkanna tinctoria Tausch," Chimika Chronika, New Series, vol. 9, No. 1, pp. 57-63 (1980).
Pardi et al.: "Renal and Urologic Complications of Inflammatory Bowel Disease." The American Journal of Gastroenterology. vol. 93, No. 4, 1998.
Pardi, Darrell S. MD, et al., "Renal and Urologic Complications of Inflammatory Bowel Disease", The American Journal of Gastroenterology, vol. 93, No. 4, 1998, pp. 504-514.
Wong, Cathy, "Rhubarb Fact Sheet", About.com Alternative Medicine, http://altmedicine.about.com/od/completeazindex/a/rhubarb.htm?p-1, Updated: Mar. 30, 2006.
Yao et al. J. of Chromatography, published online Mar. 2006, pp. 64-71. *

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